6-oxygenated 17alpha-(2-carboxyethyl)-17 beta-hydroxyandrost-4-en-3-one lactones



United States Patent 6 OXYGENATED 17a (2 CARBOXYETHYL) 17,3- HYDROXYANDROST-l-EN-li-ONE LACTONES Roy H. Bible, Jan, Morton Grove, Ill., assignor to G. D. Searle & Co., Chicago, 11]., a corporation of Delaware No Drawing. Filed May 5, 1960, Ser. No. 26,960 8 Claims. (Cl. 260239.57)

This invention relates to 6-oxygenated l7a-(2-carboxyethyl)-l7/i-hydroxyandrost-4-en-3-one lactones and processes for the manufacture thereof. More particularly, this invention relates to chemical compounds of the formula wherein Z represents a hydroxymethylene, alkanoyloxymethylene, alkoxymethylene, or carbonyl radical.

Among the alkanoyloxymethylene radicals represented by Z, especially (lower alkanoyl) oxymethylene radicals are preferred, which is to say radicals of the formula The constituent hydroxy, alkanoyloxy, and alkoxy groupings attach to carbon atom 6 of the steroid nucleus in either a or [3 configuration, depending upon the starting materials and processes of manufacture employed.

Equivalent to the described lactones for purposes of the present invention are corresponding hydroxy acids and their alkali salts, of the formula wherein Z is defined as before and X represents hydrogen, an alkali metal, or the ammonium radical. Those skilled in the art will appreciate that the salts set forth readily derive from the opposite lactones on contact with aqueous alkali. The free acids, in turn, are obtained from the salts by a critically brief exposure to a proton source; prolongation of the exposure time induces lactonization.

The compounds to which this invention relates are useful because of their valuable pharmacological properties. For example, they are potent diuretics, being adapted to block the effect of deso-xycorticosterone acetate on urinary sodium and potassium.

3,015,656 Patented Jan. 2, 1962 The 3,6-diketone and the 6a-alkoxy compounds hereof are obtained by heating corresponding 4,S-dihydro-5ahydroxy 6-ketone or 6/3alk-oxides with basic aluminum hydroxide in benzene or comparable medium to split out the elements of water. Substitution of a silica-magnesia mixture for the basic aluminum hydroxide affords the 6B-alkoxides from the indicated 6fi-alkoxy-4,5-dihydro- SOC-llYdIOXY starting materials. The 6-alkanoyloxy compounds hereof are manufactured by contacting corresponding 6[3alkanoyloxy-4,5-dihydro-5a-hydroxy lactones with dry hydrogen chloride in chloroform medium at 0, the 604 configuration being obtained if a small amount of ethanol be present, the 6,8 if not. Finally, the claimed 6-hydroxy lactones are prepared from the stereochemically apt 6-alkanoates hereof by saponification with absolute alcoholic potassium hydroxide in an inert atmosphere at room temperatures, configuration of the oxygenated grouping at carbon atom 6 remaining unchanged under these conditions.

The following examples describe in detail compounds illustrative of the present invention and methods which have been devised for their manufacture. However, the invention is not to be construed as limited thereby, either in spirit or in scope, since it will be apparent to those skilled in the art of organic synthesis that many modifications, both of materials and of methods, may be practiced without departing from the purpose and intent of this disclosure. Throughout the examples hereinafter, set forth, temperatures are given in degrees centigrade and relative amounts of materials in parts by weight, except as otherwise noted.

Example 1 17a (2 carboxyethyl)-17B-hydr0xyandr0st-4-ene-3,6 dione -lact0ne.A solution of approximately 3 parts of 1704 (Z-carboxyethyl)-5a,17B-dihydroxyandrostane-3,6- dione -lactone [obtained from 17a-(2-carboxyethyl)- 5a,6ot-epoxyandrostane-3B,17,8-diol 'y-lactone by consecutive contact in a solvent medium with aqueous sulfuric acid and chromic acid dissolved in aqueous acetic acid as detailed in Examples 1-3 of the U. S. patent application of Roy H. Bible, filed May 5, 1960, under Serial No. 26,941] in 630 parts of benzene is heated at the boiling point under reflux during agitation for 1% hours with 32 parts of basic aluminum oxide [activity grade 1, Brcckmann et al., Chem. Ber., 74, 73(1941)]. The mixture is then filtered hot, and the solids thus removed are successively washed with benzene and methylene chloride. Filtrate and washings are combined and stripped of solvent by vacuum distillation. The residue, recrystallized from methanol, melts at 222.5227.5 and has a specific rotation of -6l. This material l7u-(2-carboxyethyl)-l7fl-hydroxyandrost 4-ene-3,6-dione y-lactone, of the formula HaC Example 2 yl)50:,6oc-6POXY8I1d1'OSt3I1B-3B,17fi-di0l 'y-lactone by consecutive contact with methanolic sulfuric acid and acetonic chromic acid dissolved in aqueous acetic acid as detailed in Examples 45 of the US. patent application of Roy H. Bible, filed May 5, 1960, under Serial No. 26,941] in 180 parts of benzene is heated at the boiling point under reflux during agitation for /2 hour with parts of a 100/200 mesh mixture of silica (85%) and magnesia The mixture is then filtered hot, and the solids thus removed are washed with benzene. Filtrate and washings are combined and stripped of solvent by vacuum distillation. The residue is l7a-(2-carboxyethyl)-176-hydroxy-6,3-methoxyandrost-4-en-3-one v-lactone, of the formula Example 3 6fi-acet0xy-17a-(2 carboxyethyl)-17B-hydr0xyandrost- 4-en-3-one 'y-lact0ne.A solution of 80 parts of 6,8- acetoxy 17a-(2-carboxyethyl)-5a,17B-dihydroxyandrostan- 3-one -lactone [obtained from 17et-(2-carboxyethyl)- 5ot,6a-epoxyandrostane3/3,17B-diol 'y-lactone by consecutive contact with acetonic aqueous sulfuric acid, pyridine and acetic anhydride complex, methanolic aqueous sodium hydroxide, and acetonic chromic acid dissolved in aqueous sulfuric acid as detailed in Examples 1, 7, and 9-10 of the US. patent application of Roy H. Bible, filed May 5, 1960, under Serial No. 26,941] in 300 parts of dry redistilled chloroform is maintained at 0 in contact with a slow stream of dry hydrogen chloride for 3 hours, then washed successively with Water, aqueous 5% sodium bicarbonate, and finally water again. The solution is thereupon dried over anhydrous sodium sulfate and stripped of solvent by vacuum distillation. The residue is 6,8-acetoxy-17a-(2 carboxyethyl)-17/3-hydroxyandrost- 4-en-3-one 'y-lactone, of the formula HaC --CCHa Example 4 17a-(2-carb0xyethyl) 65,1718 dihydroxyandrost-4-en- 3-one 'y-lactone.-Approximately 400 parts of 6/8-acetoxy 17u-(2-carboxyethyl) 175 hydroxyandrost-4-en-3-one 'y-lactone is dissolved in a solution of 73 parts of potassium hydroxide in 6400 parts of absolute ethanol under a nitrogen atmosphere. The resultant solution is maintained under nitrogen at room temperatures for 2 hours, then acidified with glacial acetic acid and concentrated in vacuo to roughly yotll of its original volume. Upon dilution with water, the desired 17a-(2-carboxyethyl)- 65,17fi-dihydroxyandrost-4-en-3-one 'y-lactone is precipitated. The product has the formula Example 5 17a-(2-carb0xyethyl) 17,8 hydroxy 6a meth0xyandr0st-4-en-3-0ne 'y-lact0ne.A solution of 5 parts of l7a-(2-carboxyethyl) 5a,17[3 dihydroxy-6fl-methoxyandrostan 3-one 'y-lactone in 1800 parts of benzene is heated at the boiling point under reflux in a nitrogen atmosphere during agitation for 15 minutes with 50 parts of basic aluminum oxide [activity grade 1, Brockmann et a1., Chem. Ber., 74, 73 (1941)]. The mixture is then filtered hot, and the solids thus removed are washed with benzene. Filtrate and washings are combined and stripped of solvent by distillation. The residue, upon recrystallization from methanol, melts at 249-253.5 and has a specific rotation of -|-14. This material is 17OL-(2-C2lIbOXY- ethyl)-17l3-hydroxy-6a-methoxyandrost-4-en-3-one -lactone, of the formula Example 6 6a-acetoxy-Z 7a-(2-carb0xyethyl) 1 7 3-hydr0xyandr0st- 4-en-3-0ne 'y-lact0ne.A solution of parts of 6fi-acet- 0xy-17u-(2-carboxyethyl)-5u,17,B dihydroxyandrostan-3- one 'y-lactone in 300 parts of dry redistilled chloroform containing 1 part of ethanol is maintained at 0 for 3 hours in contact with a slow stream of dry hydrogen chloride. The solution is then successively washed with water, aqueous 5% sodium bicarbonate, and water again, whereupon it is dried over anhydrous sodium sulfate. Evaporation of solvent affords as the residue, 6a-acetoxy- 17a-(2-carboxyethyl) 17B hydroxyandrost-4-en-3-one 'y-lactone, of the formula d to Example 7 17a (2 carboxyethyl) 60:,173 dihydroxyandrost- 4-en-3-0ne 'y-lact0ne.Substitution of 400 parts of 60:- acetoxy 17a. (2 carboxyethyl) 17,6 hydroxyandrost-4-en-3-one 'y-lactone for the 6fl-acetoxy-17a-(2- carboxyethyl) 17;? hydroxyandrost 4 en 3 one 'y-lactone called for in Example 4 afiords, by the procedure there detailed, l7a-(2-carboxyethyl)-6u,17B-dihydroxyandrost-4-en-3-one y-lactone, of the formula What is claimed is: :1. A compound of the formula HaC wherein Z represents a member of the class consisting of carbonyl, methoxymethylene, acetoxymethylene, and hydroxymethylene radicals.

2. 17a (2 carboxyethyl) 17p hydroxyandrost- 4-ene-3,6-dione 'y-lactone.

wherein Z represents a methoxymethylene radical.

4. 17a (2 carboxyethyl) 1713 hydroxy 6amethoxyandrost-4-en-3-one 'y-lactone.

5. A compound of the formula \ZII wherein Z" represents an acetoxymethylene radical. 6. 6B acetoxy 17a (2 earboxyethyl) 17B hydroxyandrost-4-en-3-one 'y-lactone.

7. A compound of the formula HaC wherein 2' represents a hydroxymethylene radical. 8. 17 2 carboxyethyl) 601,175 dihydroxyandrost-4 en-3-one 'y-lactone.

No references cited. 

1. A COMPOUND OF THE FORMULA 